The invention in general relates to systems and methods for performing nuclear magnetic resonance (NMR) measurements, and in particular to systems and methods for delivering liquid NMR samples to and from flow-through NMR probes.
A nuclear magnetic resonance (NMR) spectrometer typically includes a superconducting magnet for generating a static magnetic field B0, and an NMR probe positioned in a longitudinal bore of the magnet. The NMR probe includes one or more coils for applying RF magnetic fields B1 to a set of samples of interest, and for recording the response of the samples to the applied magnetic fields. The samples of interest are inserted one at a time in the NMR probe, and NMR measurements are performed on each sample. The samples of interest are typically in liquid form.
Conventional NMR probes include stationary-sample probes and flow-through probes. In stationary-sample NMR, each sample is placed in an individual tube or vial. The vial is inserted into the NMR probe, and measurements are performed on the sample. The sample may be spun around the cylinder axis of the tube, in order to improve the resolution of the performed measurements. After desired measurements are performed on the sample, the tube is taken out of the probe and a new tube is inserted. For a description of a conventional system suitable for inserting and ejecting samples tubes from an NMR spectrometer see for example U.S. Pat. No. 3,512,078.
In flow-through NMR, the NMR probe includes a sample inlet, a sample outlet, and internal tubing extending between the inlet and outlet. The internal tubing includes a flow cell for holding the sample during a measurement. Samples are sequentially inserted into the NMR probe and flow through the internal tubing. After a measurement is performed on a sample, the sample is taken out of the probe through the tubing, and a new sample is inserted. For a description of a flow-through NMR probe see for example U.S. Pat. No. 6,177,798.
Conventionally, a robotic sample delivery system is used to deliver each NMR sample to an NMR flow probe. Sample delivery systems are commercially available, for example from Gilson, Inc. Such a system includes a robotic arm which positions a needle to a desired well of a 96-well plate containing a plurality of samples to be tested. The needle draws a desired sample into a holding loop. The robotic arm then moves the needle to an inject port connected to the flow-through NMR probe. The sample is pushed through the inject port into the flow-through NMR probe, and is taken out of the probe through the inject port after NMR measurements have been performed on the sample. The needle is moved to a different well of the 96-well plate, and the process described above is repeated for other samples held in the 96-well plate. Such a conventional system for delivering samples to a flow-through NMR probe can suffer from limited throughput and reliability problems.
The present invention provides systems and methods for performing nuclear magnetic resonance (NMR) measurements on liquid NMR samples, and for delivering the NMR samples to flow-through NMR probes of NMR spectrometers. The systems include a bypass valve capable of alternatively connecting a sample transfer conduit to a temporary sample holding reservoir, and the temporary sample holding reservoir to an inlet port of an NMR probe. In a load position, the bypass valve connects the sample transfer conduit to the temporary holding reservoir. In an inject position, the bypass valve connects the temporary holding reservoir to the inlet port of the NMR probe. The bypass valve allows the use of relatively simple and compact fluidic components for fast and reliable loading of NMR samples into the NMR probe.
In particular, the present invention provides an apparatus for performing nuclear magnetic resonance measurements comprising: a magnet; a flow-through nuclear magnetic resonance probe positioned in a bore of the magnet, the probe including an inlet port for sequentially receiving the samples, a flushing port, and internal sample tubing connecting the inlet port and the flushing port; a push solvent reservoir for holding a push solvent; a sample transfer device including a movable sample transfer conduit capable of sequential fluidic communication with a plurality of sample containers, each of the sample containers holding one of the samples; a bypass valve capable of switching between a load position and an inject position as described above; a bi-directional pump fluidically connected between the push solvent reservoir and the temporary sample holding reservoir; a temporary sample holding reservoir fluidically connected between the pump and the bypass valve; a flushing device fluidically connected to the flushing port of the probe; and control electronics electrically connected to the pump, the bypass valve, and the flushing device, for controlling the operation of the apparatus as described below.
The sample transfer conduit is positioned within a desired sample container. The pump draws a dose of liquid push solvent from the push solvent reservoir, and draws a selected NMR sample from a corresponding sample container into the temporary sample holding reservoir. During the loading step, the bypass valve is set to the load position, and the sample passes through the sample transfer conduit and the bypass valve. The bypass valve is then set to the inject position, and the pump injects the sample and the dose of push solvent through the temporary sample holding reservoir and the bypass valve into the inlet port of the probe.
As the sample is held within the probe, the magnet applies a magnetic field to the sample and NMR measurements are performed on the sample. After the measurements are completed, the flushing device provides a pressurized flushing fluid to the flushing port of the probe and the pump draws liquid from the probe, to flush the sample and the push solvent out of the probe through the inlet port of the probe. The sample is transferred into the temporary sample holding reservoir while the bypass valve is in the inject position, and then pushed out through the sample transfer device while the bypass valve is in the load position. The steps described above are achieved through the use of appropriate control signals sent by the control electronics to the sample transfer device, pump, bypass valve, and flushing device.